The overall goals of this program project are: (1) to understand the basic mechanisms in aging by the development of an integrated system for investigation ranging from the animal to the tissue to the cell to the genes and the gene products, based on the Syrian hamster. (2) To understand the basic mechanism relating aging, differentiation and carcinogenesis. There are three projects in this application: Project I, Part A, Cellular and developmental biology of mesenchymal cells of hamster and human; Part B, Nucleic acid molecular biology; Part C, Nucleic acid molecular cytology. Project II, Study on the hematopoietic system. Project III, Activation and modification of intracisternal A particle genes during senescence of mouse and Syrian hamster. The first stage is to develop the Syrian hamster as a comprehensive aging model with emphasis on mesenchymal cells in skin tissue and on hematopoietic tissue. Research will be focused on "stem" cells or progenitor cells and their differentiation from developing embryos to aged animals. The density and the function of stem cells will be used as quantitative markers for aging, and the investigation of the differentiation process will provide insight into the basic mechanism of aging. The second stage of the study is to develop the processes and to identify the factors which can manipulate differentiation, aging and neoplasia (as an aberrant differentiation process) with emphasis on the differentiation of embryonic/fetal mesenchymal cells and hematopoietic cells. The third stage of the study is the development of the molecular biological description of differentiation in terms of changes in DNA (genome) and mRNA (gene expression) allowing the testing of specific hypotheses with the aid of two new approaches, nucleic acid in situ hybridization and two-dimensional gels for separation of DNA restriction fragments. The main thrust is to detect changes in the mRNA population as related to DNA changes in sequences of intracisternal A particles, retrovirus oncogenic C particles, and common sequences between the human and hamster genomes (highly conserved in evolution). The results will indicate (1) how differentiation/aging/neoplasia can be described in terms of mRNA population and (2) how differentiation/aging/neoplasia is related to or caused by programmed or perturbed DNA changes.